This project is one component of an integrated molecular epidemiologic investigation into biomarkers of lung cancer susceptibility. The specific hypothesis of this Project is that the increased cancer risk associated with the genetic polymorphisms in metabolism noted in Project 1 is mediated by an enhanced biological response to cigarette smoke, detectable in lymphocytes as an increase in sister chromatid exchanges (SCEs) or mutation frequency (MF) at the hprt gene. We will also examine the relationship of these biomarkers with covalently bound DNA adducts in mononuclear cells and in the target tissue (lung), taking into account potential modification by heritable metabolic traits (debrisoquine hydroxylation status, aryl hydrocarbon hydroxylase inducibility and glutathione-S-transferase mu activity). This project will measure SCE frequency and hprt mutation frequency in lymphocytes from all of the cases and controls (N=660) enrolled in the study. The data will represent a very large study that employs multiple biomarkers to investigate a carcinogen-exposed population at defined cancer risk. Its integration into this Program Project will greatly augment our understanding of and ability to detect lung cancer susceptibility.